BIOMARCADORES DE BIOMARCADORES DE BIOMARCADORES DE BIOMARCADORES DE TRATAMIENTO EN LA TRATAMIENTO EN LA TRATAMIENTO EN LA TRATAMIENTO EN LA

HEPATITIS CHEPATITIS CHEPATITIS CHEPATITIS CMadrid, 13 de Mayo de 2011

Manuel Romero-Gómez. Unidad Médico-Quirúrgica de Enfermedades

Digestivas.Hospital Universitario de Valme.

Universidad de Sevilla, Sevilla.

Madrid, 13 de Mayo de 2011

Respuesta viral sostenida en genotipo 1

756975

100

SVR genotipo 1

∆∆∆∆25% +Riba ∆10∆10∆10∆10% +Peg ∆30∆30∆30∆30% +RGT

7

36

46

0

25

50

IFN 48 w I+R Peg+Riba T12PR RGT BPR RGT

McHutchinson et al. NEJM 1998; Manns et al. Lancet 2001; Fried et al. NEJM 2002; Hezode et al. NEJM 2009

Predictive factors of SVR

Viral GenotypeViral loadFibrosis

CV baja

SI

Fib leve

Gen 2/3

50% FibrosisMetabolic abnormalities

Genes

50%

CV alta

RI

Fib av

Gen 1/4

Factores predictivos de Respuesta

Manns MP, et al. Nat Rev Drug Discov. 2007Fried et al. NEJM 2002 Romero-Gómez et al. Liver Int 2011

Genotype

Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-10 00.

Impact of IR & DM on hepatitis C

HCV-core

NS5A Impairs SVR SVR

Genotype

Viral load

IRObesity

AgeSteatosis

Fibrosis

Degradation of

IRS-1

1. Pazienza V et al. Hepatology 2007;45:11642. Sheikh MY, et al. Hepatology 2008;47:21273. Moucari R et al. Gastroenterology 2008;134:4164. Romero-Gómez et al. Gastroenterology 2005;128:636

IR

Steatosis,Fibrosis

Progression and HCC

Improvement of viral fitness

Conjeevaram HS et al. Hepatology 2007;45:80-87.Manolakopoulos S et al. BMC Gastroenterol 2007;7:17 .

Insulin resistance and sustained virological response

Eslam M et al (personal communication)

INFalfa

JAK-------TyK

IFNAR1 – IFNAR2c

PTPsSOCS

Genes and SVR: IFN stimulated genes

MxA5’-2’-OASPKR

PSOCS

APO-E4

STAT

Antiviral proteins: MxA, 5’2’-OAS, PKR

Weak associations without multivariate analysis

Knapp S. Genes Immun 2003;4:411.

APO-E, IL-10, TGF-b1

Il-10: Haplotype extended:(108bp)(-2575T)(-2763C)(-1082A)(-819T)(-592A)

Allele rare < 5%

N=506

Allele rare < 5%Associated with sustained

responseConfunding factors not

excluded

Mueller T. Hepatology 2003;38:1592Yee LJ. Hepatology 2001;33:708.

HLA B 44

HLA B44 is the most prevalente HLA in caucasians

N=105 (I+R)N=143 (IFN)

caucasians

Multivariate analysis:• Genotype non-1

[OR=2.42 (1.12 – 5.55)]• HLA B44+ [OR=4.84

(1.31-17.8)]

Romero Gómez et al. Am J Gastroenterol 2003;98:1621.

RVS

SLC11A1

HFE

TNF

NRAMP2

MxAMxA

PKR

5´2-OAS

20210PT

HLA-B44

TGF-b1

APO-E

CCR5

GWAS in Hepatitis C

IL28B polymorphisms & SVR

Ge et al. Nature 2009;

Influence of IL28b CC genotype on SVR in geno 1

Ge et al. Nature 2009; Thompson et al. Gastro2010; Rauch et al. Gastro 2010;Tanaka Nature Gen 2009; Suppiah et al. Nature Gen 2009;Montes-Cano et al. Hep2010

%S

VR

Meta-analysis association SVR & genotype CC

Romero-Gómez et al. Liver Int 2010 (in press)

IL28B POLYMORPHISMS: DISTRIBUTION

BY RACE & SVR

Ge et al. Nature 2009;

IL28B mRNA expressionrs8099917

Tanaka et al. Nat Gen 2009;41:1105 Suppiah et al. Nat Gen 2009;41:1100

INF-l3 (IL28B): mechanism of action

Asselah et al. J Hepatol 2010Gad et al. JBC 2009

N=731SVC=69CHC= 284Healthy controls: 378

Montes-Cano et al. Hepatology 2010

48%

(917/1916)

68%

(590/871)

50

100

SVC

P<0.0001

IL28b and SPONTANEOUS VIRAL CLEARANCE

Rauch et al. Gastro 2010; Thomas DL et al. Nature 2009;46:798Tillmann et al. Gastro 2010; Montes-Cano et al. Hepatology 2010

589/1015202/620

(917/1916)

0

50

SVC HEP C

SVC

HEP C

SVR & IL28b IN acute Hepatitis C

N=54

Grebely et al. Hepatology 2010

n=25 n=29

IL28b and Spontaneous viral clearance

3/32

15/47

62%64%

100

TT GT/GG

SVR in treated acute Hep CN=54

Gebrely et al. Hepatology 2010

rs 8099917

0

50

TT GT/GG

n=25 n=29

Recent HCV infection

IL28brs8099917

TT

GG/GT

24 w

Peg

Peg

IL28b y Respuesta viral rápida

Influencia del genotipo de la IL28b según RVR Genotipo 1

Thompson A et al. Gastro 2010Mangia A et al. Gastro 2010

Influencia IL28b en genotipo 2/3N=488Genotipo 2rs8099917 p=ns

N=268Genotipo 2/3rs8099917

Yu et al. Hepatology 2011;53:7-13Mangia et al Gastro 2010Montes-Cano et al. Hepatology 2010

% R

VS

Influencia del genotipo de la IL28b según

genotipo viral y RVR

78% 80%

96%

86%

77%70%

88%

100%

71%

100

26%28%

33%

0

50

G1 G2/3 G1 RVR G2/3 RVR G1 no-RVR G2/3 NON-RVR

CC CT TTThompson A et al. Gastro 2010Mangia A et al. Gastro 2010

IL28b en pacientes tratados con triple terapia:IP + Peg + RibaIP + Peg + Riba

SPRINT-2: SVR by IL28B Polymorphism

7882

65

55

80

71

5960

70

80

90

100PR48 BOC RGT BOC/PR48

% S

VR

28 27

55

0

10

20

30

40

50

60

CC CT TT

% S

VR

5064

6377

4455

33116

67103

82115

1037

2342

2644

Poordad et al. EASL 2011

52

86

31

82

29

89

37

82

39

91

4340

60

80

100

Triple terapia con boceprevir. SPRINT-2: RVS en función PCR w 4 y 8.

5

3129

0

20

40

Caída PCR >1 log w4

Caída PCR < 1 log w4

PCR - w8 PCR + w8

Grupo control Triple guiada Triple 48 w

Estos resultados incluyen exclusivamente pacientes raza no negra.

Poordad F, et al. Boceprevir for Untreated Chronic HCV Genotype 1 Infection. NEJM 2011; 364: 1195-1206.

REALIZE Study Design: Patients with IL28BGenotype Data (n=527)

T12/PR48Peg-IFN + RBV

TVR + Peg-IFN + RBV

Pbo + Peg-IFN + RBV n=212 Follow-up

TVR + Peg-IFN + RBV

Peg-IFN + RBVLead-in

T12/PR48

n=210Follow-up

Pbo + Peg-IFN + RBV

484 160 128

Weeks

72

SVR assessment

Pbo/PR48

(control ) Pbo + Peg-IFN + RBV

Peg-IFN + RBVn=105

Follow-up

Data from T12/PR48 and LI T12/PR48 arms were pooled since no differences were observed between TVR arm s. Randomization was stratified by viral load and prior response. St opping rules were applied for TVR (Weeks 4, 6, 8 fo r T12/PR48, Weeks 8, 10,

12 for LI T12/PR48) and PR (Weeks 12, 24, 36 for T1 2/PR48, Weeks 16, 24, 36 for LI T12/PR48 )

Peg-IFN: Peg-IFN alfa-2a = 180 µg/week; RBV = 1000–1200mg/day TVR = 750mg every 8 hours; Pbo = placebo

Overall Baseline IL28B Genotype Distribution

63

5560

80CC

Pat

ient

s (%

)

CT TT

18 1916

29

0

20

40

Pat

ient

s (%

)

n/N=

Pooled T12/PR48

76/422

Pbo/ PR48

17/105

Pooled T12/PR48

266/422

Pbo/ PR48

58/105

Pooled T12/PR48

80/422

Pbo/ PR48

30/105

Overall SVR Rates by IL28B Genotype

CC

Pat

ient

s ac

hiev

ing

SV

R (

%)

CT TT

Pat

ient

s ac

hiev

ing

SV

R (

%)

n/N=

Pooled T12/PR48

60/76

Pbo/ PR48

5/17

Pooled T12/PR48

160/266

Pbo/ PR48

9/58

Pooled T12/PR48

49/80

Pbo/ PR48

4/30

In a 2-step multivariate analysis exploring factors including: treatment group, IL28B genotype, prior response category, treatment/prior response interaction and other baseline characteristics including baseline H CV RNA,

IL28B genotype did not have a significant impact on SVR ( p=0.169 for CC, p=0.792 for TT)

SVR Rates by IL28B Genotype and PriorResponse

88 85 85

7180

100

Prior relapsers

Pat

ient

s ac

hiev

ing

SV

R (

%)

Prior partial responders

Prior null responders

Pooled T12/PR48 (n=209)

Pbo/PR48 (n=52)

Pooled T12/PR48 (n=79)

Pbo/PR48 (n=20)

Pooled T12/PR48 (n=134)

Pbo/PR48 (n=33)

63

4033

20

58

2920 20

6

71

3130

07

0

20

40

60

80

Pat

ient

s ac

hiev

ing

SV

R (

%)

CC CT TT CC CT TT CC CT TT51/58 4/12 100/117 6/30 29/34 3/10 5/8 1/5 33/57 2/10 10/14 0/5 4/10 27/92 1/18 10/32 1/15n/N=

n/a

Camino hacia la predicción de respuesta viral sostenida

Selección de Variables:

Genotipo

Carga viral

Fibrosis

Alt. metabólicas

RVRTipo de tratamiento:

P+R

T12PR

BPR

POSIBILIDADES DE CURACIÓN

N=474 (G1/4)N=268 (G2/3)

50%

86%

91%

59%

40%

73%

82%

29%

0 50 100

S

E

VPP

VPN

G2/3 G1/4

Stättermayer AF et al. CGH 2011 (in press)Mangia et al. Gastro 2010Romero Gómez et al. Liver Int 2011 (in press)

GenotypeCC

35%

GenotypeCT

50%

GenotypeTT

15%

80%

50%

20%

SVR

28%

25%

3%

56%

Several genetic markers in 19q13.3 (IL28B)

rs12997860rs8099917rs8105790rs11881222rs7248668rs8103142

rs48032219

IlluminaAffymetrix

Interaction between IL28B & fibrosis progression

p=ns%

IL28

b ge

n C

C

Interaction between IL28B & viral loadV

iral l

oad

(log/

ml)

p=nsV

iral l

oad

(log/

ml)

Del Campo et al AASLD 2010

P=0.1

P=0.01

P=0.001

P=0.06

Association between IL28B and metabolic disturbance sm

g/dl

P=0.1mg/

dl

Del Campo et al AASLD 2010

Association between IL28b & lipid and glucose metabolism

mg/

dlm

g/dl

Del Campo et al AASLD 2010

Association between SVR & lipid and glucose metabolism

mg/

dlm

g/dl

Del Campo et al AASLD 2010

New Predictors: IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV

Factor Associated With SVR Odds Ratio (95% CI)

IL28B rs12979860 genotype (CC vs TT)

7.3

Whites (n = 871)

Ge D, et al. Nature. 2009;461:399-401.

Baseline HCV RNA (< vs ≥ 600,000 IU/mL)

1.0 10.00.1

genotype (CC vs TT)

Baseline fibrosis (METAVIR F0-F2 vs F3-F4)

6.1

5.6

Hepatitis C

Genotipo 1

Valorar factores predictivos de respuesta:

Carga viral, fibrosis, resistencia a la insulina

Genotipo no-1

Valorar factores predictivos de RVS

IL28B

CC

CT/TTTratamiento

convencional con

IFN pegilado y RBV

IP+Peg+RBV

RVR

No

RVR